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BioWorld Today: Plexxikon's Speedy Zelboraf Work Helped by Diagnostic

August 18, 2011 - BioWorld Today

Melanoma Space Changing

Given the hoopla surrounding data for Plexxikon Inc.’s targeted melanoma candidate Zelboraf (vemurafenib) earlier this year, a sooner-than-expected FDA nod for the drug and its companion diagnostic in patients with a specific BRAF mutation came as little surprise.

Even though the new drug application (NDA) submitted in May had been given six-month priority review status, the agency’s decision still came in more than two months ahead of the Oct. 28 PDUFA date. Plexxikon (now part of Daiichi Sankyo Co. Ltd.) and partner Roche AG are looking to get the drug out to patients “within two weeks,” said Krysta Pellegrino, spokeswoman for South San Francisco-based Genentech Inc., a unit of Roche. “We definitely have a sense of urgency,” she told BioWorld Today.

That need for speed has infused Zelboraf’s overall development, since the drug showed a striking 81 percent response rate in a Phase I extension study in 2009 and prompted Berkeley, Calif.-based Plexxikon to launch a single-arm Phase II study and a randomized Phase III trial simultaneously. (See BioWorld Today, Sept. 30, 2009, and Aug. 27, 2010.)

“It was a very unusual strategy,” acknowledged Kathleen Sereda Glaub, Plexxikon’s president, but it was bolstered by the availability of a diagnostic test to identify melanoma patients with the specific BRAF V600E mutation.

Plexxikon had approached Roche’s diagnostics division back in 2005. “At that time, we didn’t even have the drug in the clinic yet, so it was an interesting conversation,” Glaub told BioWorld Today. The small biotech was confident about the molecular target for the drug that would eventually become Zelboraf, but it was still a gamble to invest in a diagnostic that early in the process. “So hats off to Roche for agreeing to proceed,” she said.

So far the use of companion diagnostics in clinical development and commercialization has been a somewhat risky proposition. Despite the early success of Roche’s breast cancer drug Herceptin (trastuzumab) and its accompanying HER2 tests and the fact that the FDA has clearly stated its preference for companion diagnostics for selective therapies – last year the agency delayed a decision on ChemGenex Pharmaceuticals Ltd.’s Omapro (omacetaxine) until a diagnostic to identify patients became available – the actual development of a companion diagnostic in tandem with a therapeutic has been easier said than done.

In many cases, the trouble is that the specific mechanism of a drug is not fully understood, or at least not fully understood early enough in the development process to help convince regulators at the time of a NDA or even to improve patient screening in clinical trials. Plexxikon, which was able to use a diagnostic from the get-go, had help on both fronts.

“So it’s similar to Herceptin,” Pellegrino said of Zelboraf, a fact that could be crucial in the education of physicians, especially since the melanoma space has seen dramatic changes in only a few months.

After nearly 15 years without a new therapy for melanoma patients, Plexxikon’s drug marks the second new entrant in five months, following Yervoy (ipilimumab), an immunotherapy from New York-based Bristol-Myers Squibb Co. “We’re seeing real changes in how melanoma is being treated,” she added. (See BioWorld Today, March 28, 2011.)

And when treatment paradigms start shifting, there’s usually a learning curve for physicians, particularly when a diagnostic test is involved. But Zelboraf has an advantage going into the market because “there’s already a general awareness,”Pellegrino said.

The cobas 4800 BRAF V600 Mutation Test “has always been a part of the development of Zelboraf,” she said.

Pricing for the diagnostic will vary a bit between labs, but Roche is putting the average costs at around $120 to $150 per test and expects those costs to be covered by reimbursement plans. Zelboraf’s cost is expected to run about $56,000, which breaks down to $9,400 per month for about six months of treatment, and the drug has a good shot at reaching blockbuster status.

About 160,000 people worldwide are diagnosed with melanoma each year, and the BRAF V600E mutation occurs in about 50 percent of melanoma patients. Roche has a pending marketing authorization application (MAA) for Zelboraf in Europe.

Both the NDA and MAA were was based on interim data from the Phase III BRIM3 trial, which showed such clear overall survival and progression-free survival benefits that the study was terminated early and patients in the control arm were able to cross over to the treatment group. Updated data showed that the drug reduced the rate of death by 56 percent. (See BioWorld Today, Jan. 20, 2011.)

Those data were even strong enough to entice a buyout offer from Tokyo-based Daiichi Sankyo, which shelled out $805 million up front, even though it has only U.S. copromotion rights to Zelboraf under Plexxikon’s existing collaboration with Roche. Under the acquisition deal, Plexxikon shareholders stand to gain another $130 million in milestones tied to the drug’s commercial success. (See BioWorld Today, March 2, 2011.)

But there’s still plenty of room for improvement in melanoma treatment, and excitement is growing for the potential combination of Zelboraf and BMS’ Yervoy. The drugs work via different mechanisms of action, and “there are a number of hypotheses” for matching up Zelboraf’s remarkable early response rate with Yervoy’s slower onset, but more durable response, said Plexxikon’s Glaub. “One is that if you use Zelboraf to prime the immune system by releasing antigens [and then] bring in ipilimumab, it might be beneficial.”

In June, Roche and BMS inked a deal that will allow them to start combo studies. Pellegrino said a trial should be enrolling patients by the end of this year. Should those combination studies yield impressive data, pricing likely would become the biggest issue. Both products are costly on their own, with Yervoy running about $120,000, or $30,000 per each 3 mg/kg infusion given over three months.

Other combination studies are in the works, including Roche’s own study testing Zelboraf alongside its MEK inhibitor, hoping to improve upon the response and survival rates. Roche also is testing Zelboraf in other indications. A Phase I/II study in ongoing in thyroid cancer.

Meanwhile, Plexxikon, which operates as an independent drug discovery unit within Daiichi, continues to advance its pipeline beyond Zelboraf. Among its early stage programs is PLX3397, a kinase inhibitor targeting FMS, that is in early clinical studies in cancer.